All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Affecting over 3.2 million Americans, dry eye syndrome is a common disorder of the tear film characterized by decreased tear production. This disease is prevalent among the elderly and is particularly common in postmenopausal women. Typically, dry eye is treated using conventional drops containing small molecule drugs, although recombinant tear protein rescue for dry eye syndrome has become a possibility with the discovery of a novel human tear glycoprotein, lacritin. Lacritin is capable of promoting basal tear peroxidase secretion by rat lacrimal acinar cells in vitro, basal tear secretion by rabbit in vivo and possibly triggers downstream signaling pathway through tyrosine phosphorylation and calcium release. However, this option has found limited practical application as tears wash drugs away from the eye within minutes, and less than 2% of the medication is absorbed. As tears rapidly wash away both small and large molecule drugs, this has prevented the development of numerous protein-based drugs. By contrast, protein drugs administered to other sites in the body have continued to be developed into effective therapies. Thus, there is a clear unmet need to develop effective delivery strategies that for administration and retention of biopharmaceuticals in a target organ, such as the surface of the eye.
Accordingly, the inventive compositions and methods disclosed herein establish new and improved techniques for improving drug delivery to organs that are presently limited by biochemical and biomechanical environments due to pH, temperature, hydrodynamic flow, mechanical/structure features, among others. To overcome these obstacles, the inventors have developed temperature sensitive protein polymers and fused these polymers directly to a biopharmaceutical with enhanced therapeutic activity at the eye surface. This strategy allows for retention of drugs in the eye for much longer periods of time, on the order of days to weeks, thereby improving drug efficacy, while reducing cost and eliminating the need for repeated drug application.